Non-CD4 tropic SIV: Enhancing CD4 T-cell help in antiviral immune responses

非 CD4 tropic SIV：增强 CD4 T 细胞有助于抗病毒免疫反应

• 批准号: 8732145
• 负责人: James A Hoxie
• 金额: $ 84.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732145
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Alleles; Animals; Antibodies; Antigen-Presenting Cells; Antiviral Agents; Area; Aspartic Acid; B-Lymphocytes; Binding; Binding Sites; Blood; CCR5 gene; CD3 Antigens; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Competence; Confocal Microscopy; Defect; Disease Progression; Engineering; Epithelial; Event; Flow Cytometry; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immunohistochemistry; Immunologic Deficiency Syndromes; Immunologics; In Vitro; Infection; Infection Control; Knowledge; Label; Link; Lymph Node Cortex; Macaca; Macaca mulatta; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Molecular Cloning; Mutation; Natural History; Pathogenesis; Pathogenicity; Phenotype; Physiological; Pilot Projects; Plasma; Primate Lentiviruses; Principal Investigator; Property; Research; Role; SIV; Staining method; Stains; Subfamily lentivirinae; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tropism; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; adaptive immunity; base; cell type; cytokine; design; env Glycoproteins; fitness; immune activation; immune function; improved; in vivo; innovation; insight; macrophage; microbial; mucosal site; neutralizing antibody; novel; novel virus; programs; public health relevance; regenerative; response; simian human immunodeficiency virus

DESCRIPTION (provided by applicant): An invariant feature of HIV and SIV pathogenesis is CD4 tropism, mediated by a highly conserved CD4 binding site on the envelope glycoprotein. By focusing infection onto T-cell subsets that provide help for adaptive immunity (e.g. Th1, Th17, Tfh), it is likely that CD4 tropism has profound effects on antiviral immune responses, which are ultimately inadequate to contain viral replication and disease progression. Binding of gp120 to CD4 also has the potential to disrupt CD4's physiologic interaction with HLA class-II on antigen presenting cells, which underlies T-cell immunologic helper functions. We are exploring a highly innovative hypothesis that lentiviruses engineered to retain infectivity while lacking a CD4 binding site and CD4 tropism would be fundamentally altered in their pathogenesis, enabling more potent helper T-cell functions to be generated that are typically not permitted in the context of CD4-tropic infection. An understanding of the possible expansion in the repertoire of antiviral immune responses in this context could be informative for the HIV vaccine field. We have derived a highly CD4-independent variant of SIVmac239 and shown that it is infectious in vitro and in vivo in rhesus macaques even after its CD4 binding site has been ablated. This virus, termed "iMac-?D," replicates to a high acute peak in plasma and is then controlled to elite levels; infects macrophages and other non-T-cell types; does not deplete CD4+ T-cells; spares cortical T-cell regions in nodes; and generates high and sustained levels of neutralizing antibodies long after plasma viremia is cleared. This first non-CD4 tropic primate lentivirus will be evaluated with 4 specific aims: 1) To define and characterize in vivo its pathogenicity, tropism, and qualitative and/or quantitative differences in host humoral and cellular antiviral immune responses compared to CD4-tropic SIVmac239 infection; 2) To identify components of the host adaptive immune response responsible for iMac-?D's control and to determine if they can protect animals from a pathogenic heterologous SIV challenge; 3) To further examine the effects of CD4 interactions by evaluating pathogenicity and immunological parameters of infection when this virus retains its CD4 binding site; and 4) To extend this approach to an HIV-1 envelope glycoprotein by creating and characterizing in vitro and in vivo a non-CD4 tropic, simian/human immunodeficiency virus (SHIV) that, like iMac- D, can replicate in rhesus PBMCs and macaques while lacking a CD4 binding site. This non-CD4 tropic SHIV will provide a bridge to further studies that will be relevant to anti-HIV-1 immune responses in the setting of CD4+ helper T-cell sparing. These unique viruses and this novel model will enable us to address new and potentially paradigm-shifting themes of HIV and SIV pathogenesis and vaccine design.

描述（由申请人提供）：HIV和SIV发病机制的一个不变特征是CD4嗜性，由包膜糖蛋白上高度保守的CD4结合位点介导。通过将感染集中在为适应性免疫提供帮助的T细胞亚群（例如Th1，Th17，Tfh）上，CD4嗜性可能对抗病毒免疫应答具有深远的影响，这些免疫应答最终不足以遏制病毒复制和疾病进展。gp120与CD4的结合也有可能破坏CD4与抗原呈递细胞上的HLA II类的生理相互作用，这是T细胞免疫辅助功能的基础。我们正在探索一个高度创新的假设，即慢病毒工程保留感染性，同时缺乏CD4结合位点和CD4嗜性将从根本上改变其发病机制，使更强大的辅助T细胞功能，通常不允许在CD4嗜性感染的背景下产生。在这种情况下，了解抗病毒免疫应答的可能扩展可能为HIV疫苗领域提供信息。我们已经推导出SIVmac239的高度CD4非依赖性变体，并表明即使在其CD4结合位点被消融后，它在恒河猴体内和体外都具有感染性。这种病毒，被称为"iMac-？D "在血浆中复制到高急性峰值，然后控制到精英水平;感染巨噬细胞和其他非T细胞类型;不消耗CD4 + T细胞;保留结节中的皮质T细胞区域;并在血浆病毒血症清除后很长时间内产生高水平和持续水平的中和抗体。这第一个非CD4嗜性灵长类慢病毒将进行评估，有4个具体的目标：1）定义和表征在体内其致病性，嗜性，和定性和/或定量差异，在宿主体液和细胞的抗病毒免疫反应相比，CD4嗜性SIVmac239感染; 2）以确定组件的主机适应性免疫反应负责iMac-？D的控制，并确定它们是否可以保护动物免受致病性异源SIV攻击; 3）通过评估当该病毒保留其CD 4结合位点时感染的致病性和免疫学参数，进一步检查CD 4相互作用的影响;和4）通过在体外和体内产生和表征非CD4嗜性的HIV-1包膜糖蛋白，猴/人类免疫缺陷病毒（SHIV），其像iMac-D一样，可以在恒河猴PBMC和猕猴中复制，同时缺乏CD4结合位点。这种非CD4嗜性SHIV将为进一步研究提供桥梁，这些研究将与CD4+辅助T细胞保留设置中的抗HIV-1免疫应答相关。这些独特的病毒和这种新的模型将使我们能够解决新的和潜在的范式转移的艾滋病毒和SIV的发病机制和疫苗设计的主题。